A new ER-specific photosensitizer unravels (1)O2-driven protein oxidation and inhibition of deubiquitinases as a generic mechanism for cancer PDT.

Photosensitizers (PS) are ideally devoid of any activity in the absence of photoactivation, and rely on molecular oxygen for the formation of singlet oxygen ((1)O2) to produce cellular damage. Off-targets and tumor hypoxia therefore represent obstacles for the use of PS for cancer photodynamic therapy. Herein, we describe the characterization of OR141, a benzophenazine compound identified through a phenotypic screening for its capacity to be strictly activated by light and to kill a large variety of tumor cells under both normoxia and hypoxia. This new class of PS unraveled an unsuspected common mechanism of action for PS that involves the combined inhibition of the mammalian target of rapamycin (mTOR) signaling pathway and proteasomal deubiquitinases (DUBs) USP14 and UCH37. Oxidation of mTOR and other endoplasmic reticulum (ER)-associated proteins drives the early formation of high molecular weight (MW) complexes of multimeric proteins, the concomitant blockade of DUBs preventing their degradation and precipitating cell death. Furthermore, we validated the antitumor effects of OR141 in vivo and documented its highly selective accumulation in the ER, further increasing the ER stress resulting from (1)O2 generation upon light activation.

Copper-catalyzed Hiyama cross-coupling using vinylsilanes and benzylic electrophiles.

Allylbenzene derivatives are ubiquitous frameworks in organic chemistry. Herein is described an efficient copper-catalyzed cross-coupling reaction using vinylsilanes and benzyl bromides, leading to the synthesis of allylbenzenes. This methodology allows the use of cis, trans and 1,1'-disubstituted vinylsilanes as well as a large number of sensitive moieties.

Efficient enantioselective hydrosilylation of ketones catalyzed by air stable copper fluoride-phosphine complexes.

[reaction: see text] Copper(II) fluoride-chiral diphosphine systems catalyze the hydrosilylation of several ketones with moderate to excellent enantioselectivities. An oxygen acceleration effect was observed and led to a practical protocol with low catalyst loading.

Enantioselective pinacol coupling of aldehydes mediated and catalyzed by chiral titanium complexes.

Starting from easily available chiral Schiff bases, a straightforward synthesis of air-stable titanium(IV) complexes was devised. Asymmetric pinacol coupling of aromatic aldehydes mediated and catalyzed by the corresponding low valent complexes afforded the chiral diols with high yields and enantioselectivities up to 91%. [reaction: see text]